PROJECT SUMMARY/ABSTRACT The objective of this proposal is to understand how the first elements of olfactory circuitry are correctly wired together during embryonic development. Odorant sensing neurons project axons from the olfactory epithelium to the olfactory bulb in the brain. Each olfactory sensory neuron in the epithelium chooses a single odorant receptor to express from a very large gene repertoire. Remarkably, all of the sensory neurons that have chosen the same odorant receptor to express extend axons that converge together in specific reproducible locations within the olfactory bulb. This research proposal addresses how olfactory sensory axons so precisely locate their specific targets in the brain. This project takes advantage of the relative simplicity of the zebrafish olfactory system and its developmental and experimental accessibility to study the guidance of sensory neurons between the olfactory epithelium and the bulb. In the first aim, the hypothesis that transcription factors coordinately direct the expression of particular odorant receptors and axonal guidance receptors will be tested. This should help determine how certain groups of odorant receptors and guidance receptors are expressed together in the same sensory neurons. In the second and third Aims, axonal guidance molecules that direct the axons of olfactory sensory neurons to their specific targets in the olfactory bulb will be identified and characterized in mutant embryos. Thus far, this project has identified 12 signaling proteins that contribute to olfactory sensory axon guidance. As this project identifies additional guidance molecules, their specific functions in selective fasciculation, axon branch selection, and target field recognition will be studied in detail. These studies are building a systems level understanding of how an important functional circuit is assembled during development. This knowledge will be essential in the formulation of therapies for the regeneration and repair of olfactory circuitry in anosmic patients.